The present invention relates to medical polymers and uses thereof. More specifically, the present invention relates to polyethylene glycol derivatives having sugar residue-containing side chains and carboxyl group containing side chains, and their uses as a transporter for drugs or genes.
Drug delivery system is a therapeutic technology that controls the in vivo kinetics of drugs, delivers drugs selectively to targeted sites of action in the body, and thus realizes the optimization of therapeutic effect. Recently, studies of drug delivery systems have progressed rapidly. A great number of pharmaceutical formulations utilizing the drug delivery system technology have been commercialized, and administration methods developed by utilizing this technology have been gradually used in clinical scenes.
As drugs to be delivered by drug delivery systems, a wide range of pharmaceuticals such as anticancer drugs, drugs for the circulation system, or anti-inflammatory drugs have been studied. In these days, it is believed that drug delivery system is a technology indispensable in putting protein drugs into practical use and in realizing gene therapy.
At present, there are roughly two types of gene therapy methods actually practiced. One is a therapy method in which deficient genes in congenital genetic diseases (such as congenital immunodeficiency, inborn errors of metabolism, etc.) are complemented by introducing corresponding genes from outside. The other is a therapy method in which genes targeted to specific cells or viruses (such as cancer cells or AIDS virus) are introduced in order to inhibit propagation of or kill such cells or viruses. In both therapy methods, it is known that the important thing is to transfer a gene of interest into cells and to allow expression.
However, since DNA and cell membranes are both anionic and thus repel each other electrically, it is extremely difficult to introduce genes (DNA) alone directly into cells.
Under the circumstances, various materials have been examined as DNA carriers. However, they have problems with safety or transfer efficiency, which have prevented them from being used as DNA carriers. For example, retrovirus vectors, which are typical viral vector, have an advantage of high transfer efficiency, but have the following disadvantages: (1) they cannot transfer large size DNAs; (2) they cannot transfer DNA into non-dividing cells; and (3) the expression levels of DNAs transferred by them are low. Although adenovirus vectors are capable of transferring DNAs into non-dividing cells, they have a disadvantage of strong immunogenicity that leads to production of antibodies. Although herpesvirus vectors are excellent in DNA transfer into neurons, they have a disadvantage of strong cytotoxicity. With respect to carriers other than viral vectors, cationic liposomes, lipids, polymers, etc. have been studied. However, these materials have shown problems of low transfer efficiency or low cell specificity.
Japanese Unexamined Patent Publication No. 3-198782 discloses a method of gene transfer using a low molecular weight chitosan as a carrier. This method uses a drug that enhances the permeability of cell membranes when a gene of interest is transferred into cells. Thus, this method has a problem that cells are damaged.
The present inventors have solved the above-described problems by using a high molecular chitosan, and developed a carrier for gene transfer that can achieve a high expression level of the transferred gene and which yet is excellent in safety (Japanese Unexamined Patent Publication No. 2000-157270).
However, even in the case of using a high molecular weight chitosan as a carrier for gene transfer, there still remained problems that gene-chitosan complexes tend to aggregate and that the expression levels of genes are insufficient for therapeutic purposes.
It is an object of the present invention to provide materials that can be used as carriers for drug delivery systems and a method for preparing such materials.
It is another object of the present invention to provide carriers for drug delivery systems.
It is still another object of the present invention to provide drug delivery formulations.
Further, it is still another object of the present invention to provide carriers for gene transfer.